Mouse embryonic stem cells (mESCs) are a key component in generating mouse models for human diseases and performing basic research on pluripotency, but how many genes are essential for mESCs is still unknown. We performed a genome-wide screen for essential genes in mESCs and compared it to human cells. We found that essential genes are enriched for basic cellular functions, are highly expressed in mESCs, and tend to lack paralog genes. Notably, we discovered that genes that are essential specifically in mESCs play a role in pathways associated with their pluripotent state. We show that 25% of human genes that are intolerant to loss-of-function mutations are essential in mouse or human ESCs and that the human phenotypes most significantly associated with essential genes are neurodevelopmental. Our results provide insights into essential genes in the mouse, the pathways which govern pluripotency, and suggest that many genes associated with neurodevelopmental disorders are essential at very early embryonic stages.
